The pathogenesis of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) is characterized by the gradual loss of insulin secreting pancreatic beta cells that precedes the onset of hyperglycemia. In T1DM beta cells are destroyed by an autoimmune process. Conversely, in T2DM is the combination of different stressful insults (insulin resistance with chronic insulin hypersecretion, low-grade chronic inflammation, redox stress and hyperglycemia itself) that, progressively, destroy the beta cells, with following hyperglucagonemia. During the preclinical stage, the remaining beta cells tend to compensate for ongoing beta cell loss by increasing insulin secretion and cell replication. These compensatory mechanisms maintain near-normoglycemia but do not arrest unremitting beta cell death. Ultimately, when residual beta cell mass is reduced to about 50% of the original, hyperglycemia occurs. Theoretically, the long preclinical phase present in both T1DM and T2DM, could allow therapeutic interventions aimed at promoting beta cell survival thereby preventing the development of overt diabetes.
The diagnosis of T1DM is commonly done in the presence of fasting hyperglycemia, a positive urine ketone test, and the detection of serological markers of diabetes autoimmunity. These are autoantibodies directed against the beta cell antigens insulin (IAA), glutamic acid decarboxylase (GAD) and insulinoma antigen 2 (IA-2). With the exclusion of insulin, none of these antigens is specific for the beta cell, being expressed also by other islet cell types (IA2) and GABAergic neurons (GAD). A proportion of patients shows autoantibodies directed against unknown cytoplasmic and membrane islet cell antigens (islet cell autoantibodies, ICA and islet cell surface autoantibodies, ICSA). Early reports showed that ICSA are cytotoxic for the beta cells but the actual existence of ICSA has been recently questioned. In subjects at risk of developing T1DM (first degree relatives of patients with T1DM) is the number and titre of the different autoantibodies that predict the development of the disease. Noteworthy, none of the autoantibodies described so far is pathogenic and they appear to be the results of “antigen spreading” consequent to beta death.
The diagnosis of T2DM is often occasional. T2DM patients are usually overweight, if not frankly obese, and insulin resistant. Insulin resistance induces beta cell hypersecretion and stimulates beta cell replication but, in genetically predisposed subjects, these compensatory mechanisms are destined to fail. In these subjects, chronic beta cell overstimulation, low-grade inflammation and redox stress (all features of the insulin resistant metabolic syndrome) progressively destroy the beta cells. Beta cell death is mediated by the accumulation of cytotoxic misfolded islet amyloid pancreatic polypeptide (IAPP) oligomers. Normally, IAPP is localized on the insulin granules and is co-secreted with insulin. Under stress conditions, IAPP processing by the endoplasmic reticulum become abnormal and misfolded cytotoxic IAPP oligomers accumulate in the cell.
In addition, replicating beta cells are even more susceptible than quiescent beta cells to misfolded IAPP oligomers so that the growth of new beta cells is severely impaired. Eventually, misfolded IAPP form fibrils that precipitates in the so called amyloid deposits which are the pathologic markers of T2DM but are present already before the onset of overt hyperglycemia.
T1DM treatment is based on the administration of exogenous insulin injections. Human recombinant or synthetic insulin analogs are injected before every meal and at bedtime to replace the lack of glucose-stimulated and basal endogenous insulin secretion. Insulin injections are cytoprotective since, by putting at rest the residual beta cells, can slow their functional exhaustion. Moreover, insulin administration restores near-normal glucose levels and reduces the deadly effect that chronic hyperglycemia “per se” exerts on the beta cells (so called glucose-toxicity).
Pharmacological treatment of T2DM is based on the administration of oral hypoglycaemic agents (OHAs) which are divided into insulin sensitizers (metformin and glytazones) and insulin secretagogues (sulphonylureas and glinides). Both class of OHAs are efficacious in restoring near-normoglycemia but none of them can arrest the progressive beta cell death. This is the reason why, over time, exogenous insulin administration is often required also in T2DM patients (so called secondary failure of OHAs). Recently, it has been suggested that insulin sensitizers, by probably reducing the metabolic demand and decreasing beta cell overstimulation, can increase their life span while sulphonylureas, by acting in the opposite way, can actually accelerate beta cell death and the secondary failure to OHAs.
Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS) and is critical for essentially all physiological processes ranging from control of motor and somatosensory functions to information processing and storage. Recent studies highlight the presence of glutamate signal in peripheral tissues, and in particular in the endocrine pancreas (for a review see Skerry et al, 2001; Nedergaard et al, 2002; Hinoi et al, 2004).
At least five Na+-dependent high affinity glutamate transporters (EAAT 1-5) have been identified. EAAC1/EAAT3 and EAAT4 are expressed in neuronal cells, GLT1/EAAT2 and GLAST/EAAT1 are restricted to glial cells, whereas EAAT5 is a retina specific glutamate transporter (for a review see Danbolt, 2001). Among these, GLT1 exhibits the highest level of expression and is responsible for most glutamate transport (Rothstein et al, 1996).
An high-affinity glutamate/aspartate transporter has been cloned from pancreas (Manfras et al, 1994), and pharmacological blockade of glutamate transporters with the non-selective TBOA inhibitor has been shown to modulate glucose-stimulated insulin secretion in pancreatic islets of (Weaver et al, 1998). However, it is not yet clear whether glutamate transporters are exclusively present in islet of Langherans, whether different isoforms are expressed in a cell specific-manner, as in the CNS, and their exact physiological relevance.